A Lilly Drug Logs Success And Risks In Heart Trial

By ALEX BERENSON

Published: November 5, 2007

An experimental anticlotting drug from Eli Lilly reduced heart attacks in patients with heart disease by 24 percent compared with Plavix, the current standard treatment, according to a report released Sunday in The New England Journal of Medicine.

The experimental treatment also increased the risk of severe bleeding compared with Plavix, and quadrupled the risk of fatal bleeding, though the risk was still relatively small.

Still, Lilly and Daiichi Sankyo, the drug's co-developer, said they were pleased with the trial results. They noted that patients taking prasugrel, the new drug, reduced their overall cardiovascular risk by 13 percent even given the extra bleeding.

The companies said they planned to apply as early as the end of 2007 to the Food and Drug Administration for approval. If the F.D.A. approves the drug, it could be on the market by the end of 2008.

Both Plavix -- the world's second-best selling drug after Lipitor -- and prasugrel work in the same way, by preventing platelets in the blood from forming clots. But prasugrel is more potent, according to the results of the trial, which involved 13,000 patients who had heart disease and were receiving angioplasty.

The trial's results are promising and could clear the way for prasugrel to gain regulatory approval, according to Dr. Steven Nissen, the chairman of cardiovascular medicine at the Cleveland Clinic, who said he had been a consultant to Lilly on other drugs but not on prasugrel.

''There is a safety price to be paid,'' Dr. Nissen said, ''but I think for the majority of our patients, the benefits look like they're going to exceed the increased risk.''

But Dr. Tim Anderson, a former emergency room doctor who is now a drug industry analyst for Sanford C. Bernstein & Company, said he thought that regulators and doctors would be skeptical of prasugrel.

''Prasugrel might get approved, but I see it as more of a niche-type product,'' he said. ''Better efficacy and higher bleeding, including fatal bleeding -- it's a question mark, a serious question mark, both regulatory and commercial.''

If prasugrel is approved, worldwide sales may reach about $1.6 billion a year by 2012, Dr. Anderson said. Lilly's share of that would be about $800 million, which would represent about 5 percent of the company's annual sales. With or without prasugrel, Lilly's near-term drug pipeline is relatively weak, although the company recently reported positive trial results from a long-acting version of Byetta, its injectable diabetes treatment.

Lilly and Daiichi Sankyo also said Sunday that they will begin a new clinical trial for prasugrel next year. The trial will compare prasugrel and Plavix in 10,000 patients who have heart disease but are not receiving angioplasty.

Before the report in The New England Journal, some industry analysts and scientists had anticipated that prasugrel would fail the trial, in part because Lilly halted two other small trials of the drug last month with only a vague explanation.

The journal released the results to coincide with a presentation at a conference of the American Heart Association, which began here on Sunday.

Like Plavix, which has annual sales of $7 billion, prasugrel blocks the ability of platelets in the blood to form clumps that can cause heart attacks. But that benefit comes with a side effect. Both drugs can also increase the risk of bleeding, causing problems from nosebleeds to fatal strokes.

The trial showed that younger, healthier patients seemed to benefit most from prasugrel. Older and sicker patients were more likely to have severe bleeding while taking the drug.

Because there was a clear split between the two groups, doctors will have a relatively good idea of which patients should receive prasugrel, Dr. Nissen said.

''You can't give this drug to older, frail individuals, and you shouldn't,'' he said.

In an editorial in the journal accompanying the findings, Dr. Deepak L. Bhatt wrote that ''in carefully selected patients, prasugrel may be an advance in the treatment of patients with acute coronary syndrome.''

But Lilly and Sankyo have known for years that prasugrel faces commercial hurdles, because Plavix will lose patent protection in the United States as early as 2011 and in most of Europe by 2013. That would open the door to low-price generic versions of Plavix, and make sales potentially more difficult for the Lilly-Sankyo drug. Insurers and patients are increasingly resisting new and expensive drugs unless they show meaningful health advantages over generics.

As a result, Lilly set a high bar in the trial's design, trying to prove that prasugrel could reduce cardiac deaths, heart attacks and strokes compared with Plavix. And prasugrel succeeded.

Patients who received it had a 10 percent chance of having one of those problems, compared with a 12 percent chance if they received Plavix -- a risk reduction of 19 percent, the study said. That difference was statistically significant, meaning it was not due to chance but to a real difference between the drugs.

For heart attacks alone, the difference was even greater, with prasugrel patients 24 percent less likely to suffer a heart attack. Over all, patients taking prasugrel had 138 fewer cardiac problems than those on Plavix.

But patients also had a 2.4 percent chance of having a major bleeding episode on prasugrel, compared with 1.8 percent chance on Plavix --a 32 percent difference against prasugrel. And they had a 0.4 percent chance of suffering fatal bleeding on prasugrel, compared with a 0.1 percent chance on Plavix. Over all, 35 additional patients taking prasugrel suffered from severe bleeding compared with those taking Plavix.

Looking at patients' deaths alone, the higher bleeding deaths and reduction in cardiac deaths almost exactly canceled each other out, Dr. Bhatt wrote. He compared the risk of bleeding and heart attack to the perils of Scylla and Charybdis, the legendary monsters who threatened sailors in Greek mythology.

''There is a price to pay for greater platelet inhibition,'' he wrote.